Lincomycin-2-phosphate antibiotic compositions and process of treatment



United States Patent ,0

- LINCOMYCIN-Z-PHOSPHATE ANTIBIOTIC COMPO- SITIONS AND PROCESS OF TREATMENT Walter Morozowich and Donald J. Lamb, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware N Drawing. Continuation-impart of application Ser. No. 602,116, Dec; 16, 1966. This application Jan. 8, 1969, Ser. No. 789,915

' Int. Cl. A61k 27/00 U.S. Cl. 424-400 7 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein X is hydroxy, chlorine or bromine, R is alkyl of C cycloalkyl of C or aralkyl of C and R is hydrogen, alkyl of C cycloalkyl of C or aralkyl of C including pharmaceutically acceptable salts thereof in unit dosage form of 50 to 500 mg. with pharmaceutical carrier for oral and parenteral administration and process for therapeutic or prophylactic treatment of humans and animals hosting a lincomycin-susceptible parasite.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. 602,116, filed Dec. 16, 1966.

BRIEF SUMMARY OF INVENTION This application relates to novel compositions and process of treatment and more particularly to compositions comprising, in unit dosage form, a compound of the formula R l l' CH3 ill a? R OH SCHa 0-P-OH OH Formula 1 wherein X is hydroxy, chlorine, or bromine, R is alkyl of from 1 to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms or aralkyl of from 7 to 12 carbon atoms and R is hydrogen, alkyl of from 1 to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms or aralkyl of from 7 to 12 carbon atoms; and including the pharrnaceutically acceptable salts thereof in combination with a pharmaceutical carrier.

Typical, but not all, therapeutic compounds of this invention include the following as referred to the above Formula 1:

Do Trans n-propyl n-Pentyl Hydrogen In the above Formula 1, the vertical wavy line I is used to indicate that the group R can be in position cis (below the plane of the ring) or trans (above the plane of the ring), with respect to the carbonyl group. The horizontal wavy line is used to indicate that both epirners are to be included, i.e., the D-erythro configuration and L- threo configuration are intended.

Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl and isomeric forms thereof. Examples of cycloalkyl are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Z-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4-methylcyclobutyl, and 3-cyclopentylpropyl. Examples of aralkyl are benzyl, phenethyl, a-phenylpropyl, and a-naphthylmethyl.

The compounds of the Formula 1 can be prepared by the methods disclosed in copending application Ser. No. 602,116 filed Dec. 16, 1966.

Further, the invention relates to a process for therapeutic treatment of humans and animals hosting bacterial and other microparasites and the prophylactic treatment of a disease-susceptible host comprising the administration of a compound of the formula 1 or a pharmaceutically acceptable salt thereof to the host.

The compounds of the invention have essentially the same antibacterial spectrum in vivo as the antibiotic lincomycin and can be used for the same purposes as lincomycin. The compounds of the invention are particularly useful for oral administration to animals, including birds, because they lack the bitter taste of lincomycin.

The compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenternal solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of a compound of Formula 1 or its pharmacologically acceptable salts.

For oral administration either solid or fiuid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. The tablets can be laminated or ng the advantage of prolonged or delayed action or pre-. letermined successive action of the enclosed medication. or example, the tablet can comprise an inner dosage lIld an outer dosage component, the latter being in the mm of an envelope over the former. v

Alternatively, the two component system can be utiized, for preparing tablets containing two or more incomiatible active ingredients. Wafers are prepared in the ame manner as tablets, differing only in shape and the nclusion of sucrose or other sweetener and flavor. In their implest embodiment, capsules, like tablets, are prepared )y mixing the antibiotic with an inert pharmaceutical liluent and filling the mixture into a hard gelatin capule of appropriate'size. In another embodiment, capsules tre prepared by filling hard gelatin capsules with polyneric acid coated beads containing the antibiotic. Soft elatin capsules are prepared by machine encapsulation f a slurry of the antibiotic with an acceptable vegetable il, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such s syrups, elixirs, and suspensions can be prepared. The later-soluble forms can be dissolved in an aqueous vehicle agether with sugar, aromatic flavoring agents and preervatives to form a syrup. An elixir is prepared by using hydro-alcoholic (ethanol) vehicle with suitable sweetners such as sugar and saccharin, together with an aronatic flavoring agent.

Suspensions can be prepared of the insoluble forms /ith a syrup vehicle with the aid of a suspending agent uch as acacia, tragacanth, methylcellulose and the like.

Topical ointments can be prepared by dispersing the ntibiotic in a suitable ointment base such as petrolatum, illOliI'l, polyethylene glycols, mixtures thereof, and the ike. Advantageously, the antibiotic is finely divided by leans of a colloid mill utilizing light liquid petrolatum s a levigating agent prior to dispersing in the ointment Iase. Topical creams and lotions are prepared by disersing the antibiotic in the oil phase prior to the emulsi- :cation of the oil phase in Water.

For parenteral administration, fluid unit dosage forms re prepared utilizing the antibiotic and a sterile vehicle, ater being preferred. The antibiotic, depending on the arm and concentration used, can be either suspended or issolved in the vehicle. In preparing solutions the wateroluble antibiotic can be dissolved in water for injection nd filter sterilized before filling into a suitable vial or mpule and sealing. Advantageously, adjuvants such as local anesthetic, preservative and buffering agents can e dissolved in the vehicle. To enhance the stability, the omposition can be frozen after filling into the vial and he Water removed under vacuum. The dry lyophilized owder is then sealed in the vial and an accompanying ial of water for injection is supplied to reconstitute the quid prior to use. Parenteral suspensions are prepared 1 substantially thesame manner except that the antiiotic is suspended in the vehicle instead of being disalved and sterilization cannot be accomplished by filtraion. The antibiotic can be .sterilized by exposure to thylene oxide before suspending in the sterile vehicle.

arrier or vehicle. The specifications for the novel unit I .osage forms of this invention are dictated by and diectly dependent on (a) the unique characteristics of be active material and the particular therapeutic effect a be achieved, and (b) the limitations inherent inthe .rt of compounding such an active material for therape'iitic use in'hur'n aiis'and anlmals, as disclosed in detail inthisspecification, these beingfeatures of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, troches, suppositories, powder packets, granules, wafers, cachets, teaspoonfuls,tablespoonfuls, dropperfuls, am-

- pules, vials, segregated multipleszof any ofthe -foregoirig,

and other forms as'herein described; i1 I I *In additionto the administration ofa compoundof Formula 1 as the principal active ingredient of compositions for the. treatment of the conditions described herein, the said .co mp'ound can be 'includedIwith. other types of compounds to obtain advantageous combinationsof properties. Such combinations include -a compound of Formula 1 with antibiotics such as spectiriomycin, .clilorarnphenicol, tetracyclines( e.g., tetracycline, oxytetracycline and chlortetrachcline), penicillin, erythromyin, novobiocin, kahamycin, streptomycin, neom'ycim: polymyxin, bacitracin, nystatin, and endomycin to broaden the *bacterial spectrum of the composition and for synergistic action against particular bacteria; steroids having antiinflammatory activity such as hydrocortisone, prednisolone, methylprednisolone, fluprednisolone and "the like; analgesics such as aspirin, sodium salicylate, (acetylsalicylic acid) anhydride, acetaminophen and salicylamide; antihistamines, such as chloropheniramine maleate, diphenhydramine, promethazine, pyrathiazine, and the like; sulfas, such as sulfadiazine, sulfamethazine, sulfamerazine, sulfacetamide, sulfadimethyloxazole, sulfamethiazole, and the like, antifungals, such as undecylenic acid, sodium propionate, salicylanilide, sodium caprylate, and hexetidine; and the vitamins.

The dosage of a compound of Formula 1 for treatment depends on route of administration; the age, weight, and

condition of the patient;'and the particular disease to be treated. A dosage schedule of from about50 to 500 mg, 1 to 4 times daily (every six hours), embraces theeifective range for the treatment of most conditions-for which the compositions are efiective. For children the dosage is calculated on the basis of 6 to 8 mg./kg. by weight to be administered every six hours.

The antibiotic is compounded with a suitable pharmaceutical carrier in unit dosage form for convenient and effective administration. In the preferred embodiments of this invention, the dosage units contain a compound of Formula 1 in: 50,100, 200 and 500 mg. amounts for systemic treatment; in 0.25, 0.5, 1 2 and 5% amounts for topical or localized treatment; and 5 to 25% w./v. for'parenteral treatment. The dosage ofcompositions containing a compound of Formula 1 andone or more other active ingredients is tobe determined with reference to the usual dosage of each such ingredient.

The following examples are illustrative of the best mode contemplated by the inventors for carrying out their invention and are not to be construed as limiting.

EXAMPLE 1 Y Capsules.

One thousand two-piece hard gelatin capsules for oral use, each containing 200 mg. of lincomycin-2-phosphate are prepared from the following types and amounts of materials:

-' Lincomycin-Z-phosphate 200 Corn starch 150 Talc 75 Magnesium stearate h 2.5

500 mg. amounts by substituting 50, 100 and 500 gm. of lincomycin-Z-phosphate for the 200 gm. used above.

EXAMPLE 2 Capsules One thousand two-piece hard gelatin capsules for oral use, each containing 200 mg. of lincomycin-Z-phosphate and 250 mg. of tetracycline hydrochloride, are prepared from the following types and amounts of ingredients:

The ingredients are thoroughly mixed and then encapsulated in the usual manner.

'The foregoing capsules are useful for the systemic treatment of infection in adult humans by the oral administration of 1 capsule every 6 hours.

Using the procedure above, capsules are similarly prepared containing lincomycin-Z-phosphate and each of the following antibiotics in place of tetracycline by substituting 250 gm. of such other antibiotic for tetracycline: chloramphenicol, oxytetracycline, chlortetracycline, fumagillin, erythromycin, streptomycin, dihydrostreptomycin and novobiocin. When a penicillin, such as potassium penicillin G, is to be used in place of tetracycline, 250,000 units per capsule is employed.

Such combination products are useful for the systemic treatment of mixed infections in adult humans by the oral administration of 1 capsule every 6 hours.

EXAMPLE 3 Tablets One thousand tablets for oral use, each containing 500 mg. of lincomycin-Z-phosphate are prepared from the following types and amounts of materials:

Gm. Lincomycin-Z-phosphate 500 Lactose 125 Corn starch 65 Magnesium stearate 7.5 Lightliquid petrolatum 3 Tablets One thousand oral tablets, each containing 200 mg. of lincomycin-Z-phosphate and a total of 250 mg. (83.3 mg. each) of sulfadiazine, sulfamerazine, and sulfamethazine, are prepared from the following types and amounts of materials:

Gm. Lincomycin-Z-phosphate 200 Sulfadiazine' 83.3

Sulfamerazine 83.3 Sulfamethazine 83.3 Lactose 50 Corn starch 50 Calcium stearate 5.5

Light liquid petrolatum 5 The ingredients are thoroughly mixed and slugged. The

slugs are broken down by forcing through a number sixte'en screen. The resulting granules are then compressed into tablets, each containing 200 mg. of lincomycin-Z- phosphate and a total of 250 mg. (83.3 mg. each) of sulfadiazine, sulfamerazine, and sulfamethazine.

The foregoing tablets are useful for systemic treatment of infections by the oral administration of 4 tablets first and then 1 every six hours.

For the treatment of urinary infections, the triple sulfas in the above formulation is advantageously replaced by 250 gm. of sulfamethylthiadiazole or 250 gm. of sulfacetamide.

EXAMPLE 5 Granules 2367 gm. of a granulation suitable for reconstitution with water prior to use is prepared from the following types and amounts of ingredients:

Gm. Lincomycin-Z-phosphate 150 Tetracycline hydrochloride 150 Lecithin 5 Sucrose, powdered 2000 Flavor Sodium metabisulfite 2 The tetracycline is finely divided and coated with the lecithin. The coated tetracycline, lincomycin-Z-phosphate, sugar, flavor, and sodium metabisulfite are mixed together until thoroughly blended. The powder mixture is wetted with water and forced through a screen to form granules. The granules are dried and 23.67 gm. filled into 60 cc. bottles. Prior to use sufficient water is added to the granules to make 60 cc. of composition.

The foregoing composition is useful for systemic treatment of infection, particularly in children at a dose of one teaspoonful 4 times daily.

EXAMPLE 6 Oral syrup One thousand cc. of an aqueous suspension for oral use, containing in each 5 cc. dose, one-half gram of total sulfas and 200 mg. of lincomycin-Z-phosphate is prepared from the following types and amounts of ingredients:

Lincomycin-l2-phosphate40 gm. Sulfadiazine-33.3 gm. Sulfamerazine33.3 gm. Sulfamethazine33.3 gm.

Citric acid2 gm.

Benzoic acidl gm. Sucrose-700-gm. Tragacanth5 gm.

Lemon oil-2 cc.

Deionized water, q.s.-1000 cc.

The citric acid, benzoic acid, sucrose, tragacanth, and lemon oil are dispersed in sufficient water to make 850 cc. of solution. The lincomycin-Z-phosphate and finely EXAMPLE 7 Parenteral solution A sterile aqueous solution for intramuscular use, containing in 1 cc. 75 mg. of lincomycin-Z-phosphate is prepared from the following types and amounts of materials:

Lincomycin-2-phosphatc-75 gm. Lidocaine hydrochloride4 gm. Methylparaben-2.5 gm. Propylparaben--0.17 gm.

Water for injection, q.s.1000 cc.

-T he ingredients are dissolved in the water andthe ol1 ition sterilized by filtrationa The sterile solution ,is llledinto vials and'the vials'sealed,

EXAMPLE; 8

I Parerifeml solution w ,..A; sterile aqueous solution forintramuscula'r use, .conaimingin 1 cc. .250 mg. of lincomycin-Z-phos'phate, as he Na salt is prepared fromthe following types and mountsof-ingredientsfi .inco'myc in-2-phosphate 250 gal; lodium hydroxide 10% solution, q.s. Vater for injection, q.s..1000 cc.

The lincomycin-Z-phosphate is added to the water and ufficient sodium hydroxide added to form a solution nd the solution sterilized by filtration. The sterile soluion,v in the amount of 2 cc., is aseptically filled into terile vials and frozen. The Water is removed under igh vacuum and the vials containing the lyophilized owder are sealed. Just prior to use, sufiicient sterile later for injection to make 2 cc. of solution is added a the vial.

EXAMPLE 9 Topical ointment One thousand gm. of 0.25% ointment is prepared from nefollowing types and amounts of ingredients:

, Gm. .incomycin-Z-phosphate 2.5 inc oxide 50 Ialamine 50 .iquid petrolatum (heavy) 250 V001 fat 200 Vhite petrolatum, q.s 1000 The white petrolatum and wool fat are melted and gm. of liquid petrolatum added thereto. The linnmycin-Z-phosphate, zinc oxide and calarnine are added the remaining liquid petrolatum and the mixture milled ntil the powders are-finely divided and uniformly disersed. The powder mixture is stirred into the white ctrolatum mixture and stirring continued until the ointient con'geals.

The foregoing ointment is usefully applied topically the skin of mammals for the treatment of infection.

The foregoing composition can be prepared by omitting 1e zinc oxide and calamine.

Following the procedure above, ointments are similarly repared containing lincomycin-Z-phosphate in 0.5, 1, 2 nd 5% amounts by substituting 5, 10, 20, and 50 gm. f lincomycin-Z-phosphate for the 2.5 gm. used above.

EXAMPLE Cream One thousand gm. of a vaginal cream are prepared tom the following types and amounts of ingredients:

.incomycin-2-phosphate 5O 'egacid Regular 1 Q.. 15,0 permacetic 1 100 ropylene glycol. I 50 olysorbate 80' 5 Iethylparaben 1 Deionized Water, q.s 1000 dTheforegoing composition is useful for"the' treatment 10f vaginal infections in humans.

stirring until the temperature has dropped to;4045. C. .The pH of the final cream. is adjusted to 3.5 .by .incor- 'poration 2.5 gm. of 'citric acid and 0.2 gm. of dibasic sodium phosphate dissolved in 'about 50 gm. of water. Finally, sufiicient water is added to bring the final weight to 1000 gm. and the preparation stirred to maintain homogeneity until cooled and'congealed.

EXAMPLE 11 v -Ointment,ophthalmic One'thousa'nd gm'. of an @iithaimibi'mmemtoptaining 0.5% lincomycin-2-phospliate' are prepared from the following types and amounts of ingredients:

The antibiotics are finely divided by means of an air micronizer and added to the light liquid 'petrolatum. The mixture is passed through a colloid mill to uniformly distribute the antibiotics. The wool fat and white petrolatum are melted together, strained, and the temperature adjused to 4550 C. The liquid petrolatum slurry is added and the ointment stirred until congealed. Suitably, the ointment is packaged in one dram ophthalmic tubes. f

The foregoing ointment is usefully applied'to the eye for treatment of localized infection in humans and other animals.

Advantageously, the foregoing composition can contain 5 gm. (0.5%) of methylprednisolone for the treat- 'ment of inflammation,- and, alternatively, the bacitracin and polymyxin B sulfate can be omitted. H

EXAMPLE 12 Eye-ear drops One thousand cc. of 'a' sterile aqueous solution for eye or ear use containing 10 mg. of lincomycine2-phosphate and 10 mg. of prenisolone succin'ate sodium in each cc. is prepared fromthe following types and amounts'of ingredients: 7

Lincomycin-2-phosphate .10 gm.' Prednisolone succinate sodium-'40 gm. Sodium citrate4.5 gm. Polyethylene glycol 4000-120 gm. I Myristyl-v-picolinium 'chloride-0.2 gm. Polyvinylpyrr'o1idone1 gm. I Deionized water, q.s. ad1000 cc.

EXAMPLE 13 Track es en thousand troches are prepared from the following types and amounts of ingredients: 1 v

Lincornyclin-Z-phosphate Neomycin sulfate I 50 The powdered materials are mixed thoroughly and then compressed into half gram troches following the usual techniques for the preparation of compressed tablets.

The troches are held in the mouth and allowed to dissolve slowly to provide treatment for the mouth and throat.

EXAMPLE 14 Suppository, rectal One thousand suppositories, each weighing 2.5 'gm. and containing 100 mg. of lincomycin-Z-phosphate are prepared from the following types and amounts of ingredients:

. Gm. Lincomycin-Z-phosphate 100 'Polymyxin B sulfate (10,000 units/mg.) 1.25 fiat-methylprednisolone 1 Ethyl aminobenzoate 75 Zinc oxide 62.5 Propylene glycol 162.5 Polyethylene glycol 4000, q.s. 2500 The lincomycin-Z-phosphate, polymyxin :B sulfate, 6- methylprednisoloue, ethyl aminobenzoate, and zinc oxide are added to the propylene glycol and the mixture milled until the powders are finely divided and uniformly dispersed. The polyethylene glycol 4000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into unchilled molds at 40 C. The composition is allowed to cool and solidify and then removed from the mold and each supposity foil wrapped.

The foregoing suppositories are inserted rectally for local treatment of inflammation and infection.

Alternatively, the foregoing composition can be prepared omitting the steroid.

EXAMPLE 15 Mastitis ointment One thousand gm. of an ointment for the treatment of mastitis in dairy cattle is prepared from the following types and amounts of ingredients:

Gm. Lincomycin-Z-phosphate 50 Prednisolone acetate 0.5 Light liquid petrolatum 300 Chlorobutanol, anhydrous Polysorbate 80 5 2% aluminum monostearate-peanut oil gel 400 White petrolatum, q.s. 1000 Animal feed One thousand gm. of a feedmix is prepared from the following types and amounts of ingredients:

Gm. Lincomycin-Z-phosphate Soybean meal 400 Fish meal 400 Wheat germ oil 50 Sorghum molasses 140 The ingredients are mixed together and pressed into pellets.

The composition can be fed to laboratory animals, i.e.,

rats, mice, guineas pigs, and rabbits for prophylaxis during shipping. a

For larger animals, the composition can be added to the animals regular feed in an amount calculated to give 'the desired dose of lincomycin-2-phosphate.

:EXAMPLE 17 Following the procedure of each of the preceding Examples 1 and 3, each member selected from the group consisting of sodium novobiocin, calcium novobiocin, chlortetracyline hydrochloride, oxytetrac'ycline hydrochloride, tetracycline, tetracycline hydrochloride, and tetracycline phosphate complex is added "in 50, 100, and 250 gm. amounts to provide a combination having a wider spectrum of therapeutic effectiveness in the treatment of infectious diseases resulting frornfimixed organisms susceptible to lincomycin-Z-phosphate as indicated in the present specification and the above indicated antibiotics as already well known to the medical art.

EXAMPLE 18 EXAMPLE 19 Following the procedure of the preceding Examples 1 through 5, '9 through 11, and 13 through 16, inclusive, each member selected from the group consisting of 7 (S) -chloro-7-deoxylincomycin-Z-phosphate, calcium salt, 7 (S )-chloro-7-deoxylincomycin-2-phosphate, magnesium salt, 7(S)-chloro 7 deoxy-1'-demethyllincornycin-2-phosphate, calcium salt, or 7 (S)-chloro 7 deoxy-1'-demethyllincomycin-Z-phosphate, magnesium salt is substituted in an equivalent amount for the lincomycin-Z-phosphate shown in the example and provides similar therapeutic properties.

What is claimed is: 1. An antibacterial composition comprising, in unit dosage form, from about 50 to 500 mg. of a compound of the formula:

R1 C-N- Wgt.

wherein X is hydroxy, chlorine or bromine, R is alkyl of C cycloalkyl or C or aralkyl of C and R ion of the compoundof ,t a is from about 0.25% v./w. to about 25% wjw. -j3, ;\A\:-eornposition iiOfiLiClfliIIl: Lwherein: zth edleoncentraion of thel-lcompoundwfr therformula is from about;

- 4: A' proees fo treating acterialdisease in' umans ind animals which eomprisesadministering =1to,th e bacerial host an antibacterial therapeutic amountxof a c'om- )oundof the formula: 1 w

vherein" X is'hydro'xy, 'chlorineor bromine, R is alkyl )1? C cycloalkyl of C or aralkyl of C R is lydrogen', alkyl of C cycloalkyl of C or ar'alkyl )f C5 or'pharmaceutically acceptable salts thereof in :ombination with a pharmaceutical carrier.

5. A process'according to claim 4 wherein the com- )Olllld of the formula is administered in unit dosageform 1-. herein-.the u concentras.

in anarnounfiof'irom about 5,0.to about'500 mg. offsaid 'COHIPQUIKIZ in association with-a pharmaceuticalcarrier. process or prophylactic treatment for, thGjPI'CYfiIltion of bacterial disease comprising the administering .;-to

aa diseasevsusceptiblejhuman for animal host a prophylactic 5; antibacterial; amountof a compound 0f:the iormulaz 1 pound of the formula is adtr'rinistered in unitdosage form in an amount of from about. to about 500 mg; of said "compound in association with a pharmaceutical carrier;

5 References Cited V U TED STATES PATENTS l 3,150,042 9/1964 "Bless a all 424 274 3,268,556 8/ 1966 Hoeltsema, 424-274 ALBERT T. MEYERSI, i tiaaryiaaainer. a g

I. D. GOLDBERG, Assistant Examiner 

